Cobimetinib (XL518, GDC-0973) is an oral small molecule MEK inhibitor developed by Roche. Cobimetinib is designed to selectively block the activity of the MEK protein, thereby blocking its downstream signaling pathways. The drug was first approved by the Swiss Bureau of Drug Administration in August 2015 and was approved by the US FDA to come into the market in November 2015 for the treatment of unresectable or metastatic melanoma in combination with Zelboraf. Since the drug does not have a standard Chinese name, the applicant transliterated it as “kabitini”.
The chemical name of cobimetinib (I) is: [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy-3-(2 S)-2-piperidyl-1-azacyclo-butyl]methanone, and its structural formula is:

The synthesis of cobimetinib (I) has been reported in the literature. From its structural analysis, it can be seen that the difficulty in the synthesis of the compound is mainly reflected in how to obtain the chiral group in the molecular structure quickly, economically and with high purity. There are two main routes for the preparation of the compound at present.
PCT patents WO2007044515, WO2008076415, WO2008124085, and “ACS Medicinal Chemistry Letters” 2012 Vol. 3, No. 5, pages 416-421 et al. reported a synthesis method of cobimetinib (I). The above literature has some changes in the side chain linking method, such as: firstly forming a trifluorophenyl acylate, and then substituting one of fluorine atoms with another aniline containing fluorine and iodine to complete the linking of the entire side chain (fractional-step method); or firstly preparing benzoic acid or acyl chloride containing two substituted benzene ring side chains, and performing amidation reaction to obtain cobimetinib (one-step method). However, the core chiral intermediate (II) is prepared by firstly preparing a racemate and then performing chiral resolution by using a resolving agent (R)-alpha-methoxy-alpha-trifluoromethylphenyl-acetyl chloride, thereby obtaining the desired S-configuration target intermediate (II). From the perspective of the reaction process and yield, due to the need for repeated resolutions of at least 3 times, the steps are quite complex, a large amount of resolving agents and other auxiliary materials are needed, and the highest resolution yield is only 50%, thereby limiting the industrialization of the process.

The PCT patent WO2014059422 describes another preparation method of cobimetinib (I) and analogs thereof, which abandons the low-efficient resolution method, but uses chiral amino alcohols as a chiral inducing reagent, making it more convenient and economical for obtaining chirality. However, the chiral inducing reagent (raw material) containing nitrile group is difficult to obtain, the strong alkali lithium diisopropylamide is unstable, and ultralow temperature (−78° C.) and absolutely water-free oxygen-free reaction conditions are needed, thereby also limiting the industrialization prospect of the synthesis route.

In view of the defects in the existing process, the development of a simple, economical, environment-friendly and high-quality preparation technology, in particular the seek for a technology capable of adapting to industrial production, has important practical significance on the improvement of the economic and social benefits of the drug.